In Oct. 2012, the Health IT Policy Committee, which advises the Office of the National Coordinator for Health IT, released preliminary recommendations for Stage 3 meaningful use requirements for electronic health records (EHRs). Included in those recommendations are a requirement that certified EHRs (those that are eligible for federal incentive payments) be capable of reporting adverse drug events to FDA and/or the Centers for Disease Control and Prevention. If the recommendations receive final approval, which is expected this April, drug companies could see a surge in AE reporting start in 2016, when Stage 3 requirements begin to take effect.
Meanwhile, FDA continues to work toward an active drug safety surveillance system through its Sentinel Initiative, which was mandated by the FDA Amendments Act of 2007, and its Mini-Sentinel pilot project that has secure access to records of more than 126 million patients nationwide from 17 data sources. Further adding to the volume of AE data is an increasing focus on social media as a source for finding out about adverse events.
“We’re going to see an evolution of change in pharmacovigilance over the next five to 10 years,” says Elizabeth Garrard of Garrard Safety Solutions (Chapel Hill, NC). “Individual case study reports and the pressures we have today will be different, largely alleviated by tremendous automation and other technological advances” that will allow us to extract better quality data out of a greater volume of adverse event reports and, ultimately, detect safety signals earlier.
EHRs notwithstanding, the number of adverse events reported to FDA has grown steadily since 2002, approaching 800,000 in 2011, and projected to top that for 2012 (see Fig. 1).
FDA requires pharmaceutical companies to report AEs that meet four basic criteria: an identifiable patient; an identifiable reporter; a specific drug; and a symptom or effect. Per FDA rules, pharmaceutical companies also are required to provide the agency with a complete dataset about the event, a process that often involves following up with the patient and healthcare provider. Trained investigators categorize the symptoms and possible causes, and sometimes involve the prescribing physician as well. What FDA and pharmaceutical companies are most concerned about are AEs that are categorized as both serious and unexpected. These are the ones that most often lead to label changes and product withdrawals.
Traditionally pharma companies had their own staffs to handle the initial reports and followup interviews. As with other pharma industry duties, many companies now outsource that function, or employ a hybrid model of both internal and external resources. According to Greg Fiore, chief medical officer for The Medicines Company (Parsippany, NJ), most pharmaceutical companies, including his, employ a hybrid model. “We focus in-house resources on the most strategic and highly scientific jobs, while outsourcing technical operations,” he says. “I think what you see throughout the industry is consistent with that.”
APCER Pharma was founded in 2007 with the intent to provide global AER services—“something we identified as lacking in other specialty providers,” says Gaurav Saxena, manager of operations and business analytics for the Princeton, NJ, firm. The company handles AERs from more than 80 countries. (FDA requires drug companies to report all adverse events, even foreign ones, for any drug available in the United States.)
Another differentiator for APCER is its utilization of offshoring certain functions to provide clients with low-cost solutions without sacrificing quality. “We have offices located in the US, Europe and Asia, but we are one team and our operations are seamless,” Saxena says. But APCER also recognizes that not all drug companies are comfortable with the idea of offshoring. “It has become an important option to pharmaceutical companies that need to maintain their high standards for regulatory compliance while containing costs,” Saxena says. “Other companies prefer a hybrid model, where the initial phone call or response takes place in the US or EU, then the adverse case is processed in the Asia office. There are still some companies that prefer a model where everything is handled onshore.”
Another AER service provider is BioSoteria (Emeryville, CA), which became a property of Dohmen (Milwaukee) in April 2012 and absorbed the client portfolio of an existing AER service, DDN Medical Affairs, to become Dohmen Safety. Sally VanDoren, who founded BioSoteria and oversees Dohmen Safety, which also includes call center company MedComm Solutions, says the company provides adverse event reporting and drug safety services to more than 200 pharmaceutical and biologic companies. “The merger allowed us not just to collect the information and provide a healthcare-staffed call center, but we also have the expertise of interpreting the information, communicating the risk, and updating the product label,” VanDoren says.
Drug Safety Alliance (Durham, NC) is another company that recently added to its service offerings following a merger. In August, the company was acquired by United Drug (Dublin, Ireland), an international healthcare services provider. In addition to performing activities related to the reporting and analysis of adverse events, the company now boasts call center services, thanks to a partnership with fellow United Drug company Alliance Healthcare Information (Ivyland, PA).
Other companies in the outsourced AER business include PROSAR (St. Paul, MN) and Sentrx Safety Solutions (Little Falls, NJ), among others. Most clinical research organizations (CROs) provide pharmacovigilance services, and many of them continue the services into post-marketing trials and compliance.
Preparing for EHRs (and large sets of data)
The Stage 3 requirements for meaningful use of EHRs require systems to have the capability to report AEs, but the Health IT Committee, so far at least, has made no mention of a minimum number of AEs that need to be reported by healthcare providers in order to be compliant. Currently, reporting of AEs by healthcare providers is voluntary. The number of AEs reported to FDA by healthcare providers is rising (see Fig.), and many drug safety experts believe that EHRs will increase that volume even more.
A 2009 study sponsored by Pfizer looked at the impact pre-populated AE reporting forms in EHRs would have on the reporting process. The seven-month ASTER (ADE Spontaneous Triggered Event Reporting) study found that 91% of the 30 ambulatory care physicians who participated in the study had submitted no adverse event reports in the prior year. During the study, participants reported an average of approximately five reports in a three-month time period. All study participants reported at least one adverse event. And of the more than 200 adverse events reported through the ASTER study, approximately 20% were deemed serious.
EHRs likely will increase the volume of reports, but will the quality of those reports increase as well? Garrard of Garrard Safety Solutions believes it will. “Consumers sometimes muddy the waters when reporting an AE, requiring you to follow up with the healthcare provider,” she says. “With EHRs, the AE would be validated by a healthcare provider right off the bat, not to mention it would be linked to a patient’s healthcare record.”
But Edward Fotsch, MD, CEO of PDR Network (Montvale, NJ) sees the potential for more work for manufacturers and their safety teams. “Even when integrating EHRs, over 70% of the time, the company has to get back in touch with the reporter to get additional information about that event,” he says. “What you don’t want to do is simply increase the volume of crummy reports going to the manufacturer.”
PDR Network’s RxEvent product, a Web-based AER system that allows reporting through EHRs, is live in four EHR systems. Fotsch says the company is working on allowing manufacturers, for a fee, to customize their reporting forms for each drug in the EHRs. “What one-size-fits-all form makes sense? Almost by definition, that means you’ll ask certain questions that don’t make any sense and you’re going to skip questions that are really important,” he says. “We believe this customization is key, because for every drug, there may be some extra piece of information that the manufacturer needs” to have a complete dataset.
EHRs aren’t the only untapped source for AEs. FDA’s Sentinel Initiative, which was authorized by the FDA Amendments Act of 2007, is developing an active surveillance system allowing the agency to query a variety of automated healthcare data holders—e.g., EHRs, administrative and insurance claims databases, and health registries—to discover possible drug safety issues sooner and potentially, with some degree of automation. Through this system, the health data continue to be managed by its owners, who evaluate Sentinel’s queries and send summary results to FDA.
As of last July, FDA had used its Mini-Sentinel pilot program to conduct more than 120 data requests to gather safety information on various FDA-regulated products. According to FDA, over the coming year, the agency will further expand this capability to allow for more “routine” surveillance on more products. Garrard says it’s unclear if manufacturers will have access to these health databases to do their own safety signaling work.
According to FDA, the Sentinel system is intended to supplement, not replace, FDA’s current surveillance tools, which include the recently launched FDA Adverse Event Reporting System (FAERS). Replacing FDA’s previous reporting system (AERS), which consisted only of a transactional database, FAERS contains both a transactional database that will be used primarily for data entry, as well as a new business intelligence solution (FBIS) that will allow users to create complex queries and customized reports. “FBIS provides enhanced analytical capabilities to transform large datasets like FAERS into meaningful information, so FDA can better evaluate trends, and make timely and informed decisions about the safety of marketed products,” says the agency.
Finding meaning in AEs reported to FDA was the founding mission for Adverse Events, Inc. (Healdsburg, CA), which applies a proprietary 17-step data refinement process to FDA’s MedWatch database, which is updated quarterly with AE reports submitted voluntarily by healthcare professionals, consumers and patients. Including historical data dating back to 1997, the company has access to four million unique adverse event cases covering approximately 4,500 drugs and more than 500 million unique data points to query. The company releases regular analysis on new drugs, trending drugs, and drugs with most reports during the previous quarter, as well as in-depth research reports, in order to attract attention to its methodology from manufacturers, and the payer and provider markets.
“We market our services primarily as an enterprise offering to pharmaceutical companies, either on a project/consulting basis or purely as a data supplier,” says Brian Overstreet, president. “In most cases, we are acting as an adjunct to an established drug safety unit or service, as an outsourced pharmacovigilance resource.”
But mining large databases for safety signals is not always going to be the best solution. As Dohmen Safety’s VanDoren points out, “More and more drugs are becoming specialized, and when you’re talking about orphan drugs for patients with rare diseases, you won’t be able to just jump into a database to find your answer. Longitudinal studies will be far more valuable.”
Finding AEs online
Another potentially vast source for AEs is the Internet, namely patient comments scattered across social media, mobile health apps and brand-sponsored websites. Manufacturers have the obligation to monitor their own websites and any other branded pages, including Facebook, Twitter or brand-sponsored patient support groups, for AERs.
The problem is companies lack formal guidance from FDA on what to do with AEs reported through these channels. In Dec. 2011, FDA issued draft social media guidelines about responding to unsolicited requests about off-label uses of drugs, but it made no mention of adverse events. That should change soon, since the Food and Drug Administration Safety and Innovation Act (PDUFA V), signed into law in July 2012, requires FDA to issue social media guidance by July 2014. And FDA has indicated that one of its new initiatives is exploring new data sources for adverse events, including social media.
Part of the challenge of monitoring social media for AEs is turning large amounts of information into useful data. Today, there’s a variety of listening tools available that allow companies to filter out the noise and hone in on reportable events. “The critics will say it’s just a bunch of hooey and it’s not meaningful,” Garrard says. “In some cases, that may be true, but in others, you’re missing that opportunity to find that nugget. A good listening platform picks up on those nuggets and filters out the noise.”
One such tool is AETracker, from Semantelli (Bridgewater, NJ). Originally conceived as a Facebook listening tool for pharmaceutical companies interested in collecting adverse events, as well as off-label comments and product misinformation on their branded Facebook pages, AETracker also can be used to monitor any brand-sponsored social media or mobile patient applications.
Semantelli CEO, Siva Nadarajah says there’s a huge need for collecting adverse events in these channels, thanks to a proliferation of mobile health apps and worldwide penetration of Facebook. (According to digital analytics company comScore, there are only six countries where Facebook is not the dominant social networking tool.)
Currently, eight pharmaceutical companies, including the largest consumer OTC manufacturer, are using the service, which automatically monitors sites for specific adverse event terms—identified by what’s published by FDA and academic institutions, as well as terms suggested by the pharmaceutical companies. Each potential adverse event is then validated by support personnel at Semantelli before being sent to the client. Semantelli also can handle reporting directly to FDA on behalf of the client.
In the past year, AETracker has detected more than 12,000 potential adverse events from social media, out of which about 3,000 were qualified as reportable to FDA. In the same time period, Nadarajah says AETracker helped detect and report more than 600 adverse events from the OTC manufacturer’s sponsored Facebook brand page, which has 200,000 fans.
Another challenge facing manufacturers with an online presence is making sure that branded programs are designed with the knowledge that they could produce reportable AEs. The European Medicines Agency (EMA) opened an investigation last year into Roche’s handling of AEs reported through a US-based patient support program (PSP). In a previous investigation, the UK’s Medicines and Healthcare Products Regulatory Agency found that the company failed to evaluate about 80,000 adverse events, including more than 15,000 deaths, collected through the PSP, to determine if they were events that should have been reported to EU authorities. FDA says it has been working with Roche since last spring to assure the orderly reporting of the late AERs identified by EMA during its inspection.
While the cause for the under-reporting of these AEs is unknown, Garrard says it serves as a good reminder to manufacturers to develop PSPs and other branded programs with pharmacovigilance in mind. “You can’t just go off and do a marketing campaign or patient assistance campaign without recognizing that you’re going to get safety information in return,” she says. “That information needs to go somewhere, and typically it needs to go to pharmacovigilance. When developing these programs, companies need standards in place for routing that information through the appropriate channels.”
Adapting to all of these changes in pharmacovigilance will require a paradigm shift, says Fiore of The Medicines Company. “We can no longer apply the old paradigms, which focus on single case reports,” he says. “We’re going to see a higher volume of data, but, best case scenario, it will be more useful and less costly. That’s the change that’s afoot in pharmacovigilance.”